Midkine induces tumor cell proliferation and binds to a high affinity signaling receptor associated with JAK tyrosine kinases.
The G401 cell line derived from a rhabdoid tumor of the kidney secretes the heparin-binding growth factors midkine and pleiotrophin. Both proteins act as mitogens for diverse cells, but only midkine serves as an autocrine mitogen for G401 tumor cells. We show that midkine specifically binds a protein or complex of molecular mass greater than 200 kDa with high affinity (Kd = 0.07 +/- 0.01 nM). Midkine, but not pleiotrophin, stimulates tyrosine phosphorylation of several cellular proteins with molecular mass of 100, 130, and 200+ kDa. Upon midkine binding, the midkine-receptor complex associates with the Janus tyrosine kinases, JAK1 and JAK2. MK stimulates tyrosine phosphorylation of JAK1, JAK2, and STAT1alpha. Our initial characterization of the midkine receptor suggests that midkine autocrine stimulation of tumor cell proliferation is mediated by a cell-surface receptor which in turn might activate the JAK/STAT pathway.
Ratovitski
E A
EA
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. erat@welchlink.welch.jhu.edu
Kotzbauer
P T
PT
Milbrandt
J
J
Lowenstein
C J
CJ
Burrow
C R
CR
D000818:Animals; D002352:Carrier Proteins / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D016207:Cytokines; D004789:Enzyme Activation; D006801:Humans; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D000078792:Midkine; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D016207:Cytokines; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D000078792:Midkine; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2